慢性B细胞受体（BCR）信号、致癌的CARD11基因或API2-MALT1（也称为BIRC3::MALT1）融合致癌蛋白所依赖的恶性淋巴瘤中，恒定的MALT1活性促进了细胞的存活。虽然MALT1的支架作用诱导了NF-kB依赖的存活信号，但MALT1蛋白酶活性因在B细胞淋巴瘤中裁剪信号传导介质和转录调控因子而增强了NF-kB的激活，对于MALT1蛋白酶活性在淋巴瘤发生中的病理作用尚不清楚。在本研究中，我们展示了TRAF6控制了MALT1依赖的NF-kB转录反应的激活，但对由致癌CARD11推动的MALT1蛋白酶的激活是不必要的。为了解耦MALT1的酶活性和非酶活性功能，我们分析了在致癌CARD11和API2-MALT1推动下，TRAF6依赖和非依赖以及MALT1蛋白酶依赖的基因表达谱。数据暗示，通过裁剪并失活RNA结合蛋白Regnase-1和Roquin-1/2，MALT1蛋白酶在活化的B细胞样弥漫大B细胞淋巴瘤（ABC DLBCL）中诱导了NFKBIZ/IkBz、NFKBID/IkBNS、ZC3H12A/Regnase-1等多个基因的后转录上调。我们证明，由癌基因驱动的MALT1活性在ABC DLBCL细胞中通过释放Regnase-1和Roquin-1/2施加的制动，调控了NFKBIZ和NFKBID基因在mRNA水平上的表达。此外，MALT1蛋白酶在与粘膜相关的淋巴组织（MALT）淋巴瘤中，通过引起复发性t（11；18）（q21；q21）易位所创建的API2-MALT1融合基因上下文中诱导了后转录基因表达。因此，MALT1副半胱氨酸酶在增强恶性淋巴瘤的转录和后转录基因表达的分岔点起到了作用。此外，识别MALT1蛋白酶选择性靶标基因为MALT1抑制剂的临床评估提供了特定的生物标志物。Copyright © 2023 American Society of Hematology.

Constitutive MALT1 activity drives survival of malignant lymphomas addicted to chronic B-cell receptor (BCR) signaling, oncogenic CARD11, or the API2-MALT1 (also BIRC3::MALT1) fusion oncoprotein. While MALT1 scaffolding induces NF-kB-dependent survival signaling, MALT1 protease function is thought to augment NF-kB activation by cleaving signaling mediators and transcriptional regulators in B-cell lymphomas. However, the pathological role of MALT1 protease function in lymphomagenesis is not well understood. Here, we show that TRAF6 controls MALT1-dependent activation of NF-kB transcriptional responses, but is dispensable for MALT1 protease activation driven by oncogenic CARD11. To uncouple enzymatic and non-enzymatic functions of MALT1, we analyzed TRAF6-dependent and -independent as well as MALT1 protease-dependent gene expression profiles downstream of oncogenic CARD11 and API2-MALT1. The data hint that by cleaving and inactivating the RNA binding proteins Regnase-1 and Roquin-1/2, MALT1 protease induces post-transcriptional upregulation of many genes including NFKBIZ/IkBz, NFKBID/IkBNS and ZC3H12A/Regnase-1 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). We demonstrate that oncogene-driven MALT1 activity in ABC DLBCL cells regulates NFKBIZ and NFKBID induction on mRNA level via releasing a brake imposed by Regnase-1 and Roquin-1/2. Furthermore, MALT1 protease drives post-transcriptional gene induction in the context of the API2-MALT1 fusion created by the recurrent t(11;18)(q21;q21) translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. Thus, MALT1 paracaspase acts as a bifurcation point for enhancing transcriptional and post-transcriptional gene expression in malignant lymphomas. Moreover, the identification of MALT1 protease selective target genes provides specific biomarkers for the clinical evaluation of MALT1 inhibitors.Copyright © 2023 American Society of Hematology.